Natural products represent a very significant platform for the development of new drugs and provide a continuous stimulus for research in all areas of science, including chemistry, biology and medicine. The objective of the proposed research is to study methods and develop synthetic strategies that would permit an efficient and stereocontrolled chemical synthesis of representative members from two families of bioactive natural products: the zoanthamine alkaloids and the cembranolides. The targeted natural products have uncommon chemical structures, potent biological activities and unexplored biological modes of action, which attest to their potential as new biological tools and leads for drug development. The proposed methods stem from the unexplored reactivity of electronically rich species, such as dienes and furans, during cycloaddition reactions and highlight the potential of these reactions for the construction of highly functionalized heterocycles. The proposed strategies will test the scope and limitations of the above methods and evaluate their applicability in natural product synthesis. The strategies are also designed to create structural complexity from relatively unfunctionalized starting materials by incorporating multiple carbon-carbon bond forming events in one step. These strategies will pave the way for the synthesis of simplified analogues of the natural products that, in combination with the parent structures, will be used to interrogate the biology of the new chemical structures and translate their chemical reactivity to biological mode of action. PUBLIC HEALTH RELEVANCE: We describe a research program toward the synthesis on two classes of bioactive marine natural products: the zoanthamine alkaloids and the cembranolides. The selected targets have interesting chemical structures and very potent bioactivities as lead structures for the development of new pharmaceuticals. We propose to explore a strategy toward the synthesis of zoanthamines that is inspired by a biosynthesis hypothesis. Our preliminary results suggest that it is possible to synthesize these complex natural products starting from an acyclic precursor by tuning a polycyclization reaction cascade. We plan to explore this reaction cascade for the synthesis of new polycyclic motifs and apply it to the synthesis of zoanthenol. In addition to the synthetic achievements, the results of our study are expected to have great impact in the areas of synthetic methodology, in particular to the reactivity of 2-aminodienes. We also propose to develop a unified approach toward the synthesis of selected cembranolides that is based upon the unexplored reactivity of 1-epoxyfurans. The synthesis of these compounds will pave the way for evaluation of their biological and pharmacological profile that will be pursued in collaboration with experts in the field.